6alpha-methyl-3-oxo-delta4-steroids of the androstane and pregnane series



United States Patent 3,270,037 6a-METHYL-3-0XO-A -S'1ER01DS OF THEANDRO- STANE AND PREGNANE SERIES Winifred June Adams, Bernard Ellis,Vladimir Petrow,

and Isobel Ann Stuart-Webb, London, England, assignors to The BritishDrug Houses Limited, London, England, a British company No Drawing.Filed June 19, 1956, Ser. No. 592,243 Claims priority, application GreatBritain, June 22, 1955, 18,118/55 7 Claims. (C1. 260-3973) Thisinvention is for improvements in or relating to organic compounds andhas particular reference to new 6e-methyl-3oxo-A -steriods of theandrostane and pregnane series.

It is an object of the invention to provide new compounds of theandrostane and pregnane series which are of value on account of theirbiological properties, for example as anabolic or progestational agents.

The invention provides new 6a-methyl-3-oxo-A -steroids of the androstaneand pregnane series having the general formula Me and in particular thecompounds 17 3-hydroxy-6a-methylandrost-4-en-3-one(6a-methyltestosterone), 17fi-hydroxy- 6a:l7a-dimethylandrost-4-en-3-one (6a: l7a-dimethyltestosterone17a-etbinyl-l7p-hydroxy-6a-methy1androst-4- en-3-one (6a-methylethisterone), and 6a-methylpregn-4- ene-3 20-dione(6a-methylprogesterone).

According to the present invention there is provided a method for thepreparation of 6a-methyl-3-oxo-A -steroids of the androstane andpregnane series having the general Formula I above, which methodcomprises treating a 3p:5a-dihydroxy-6a-methyl steriod of the androstaneand pregnane series having the general formula with an aluminiumalkoxide in cyclohexanone/toluene under reflux. With the use of e.g.aluminium tert.- butoxide in cyclohexanone/toluene under reflux (Le. theOppenauer oxidant), oxidation occurs at the 3 position, accompanied bydehydration of the a-hydroxyl group to give a GtI-methyl-3-oxo-A-steriod which will undergo epimerisation at C to give the6a-methyl-3-oxo-A -steroid.

Alternatively, the 3/1:5a-dihydroxy-6f3-methyl steroid of the nndrostaneor pregnane series may be converted into the desired 6a-mcthyl-3-oxo-A-ste-roid via the 618- methyl-3-oxo-A -steroid by epimerisation. The6B-methyl-ft-oxo-M-steroid may be treated with an alkaline reagent, e.g.potassium hydroxide, or an acidic reagent, e.g. hydrochloric acid, in,for example, an aqueous organic solvent mixture such as aqueous alcoholunder reflux and under nitrogen for several hours, when epimerisation ofthe 6fi-methyl group occurs.

3,270,037 Patented August 30, 1966 The 3B:5a-dihydroxy-6f3-methylsteroid of the androstane or pregnane series may also be converted intothe 60t-fl16ihYl-3-OX0-A SiCrOld via the 3B-hydroxy-6fl-methyla-steroid. The 3fl-hydroxy-fifi-methyl-a -steroid may be oxidised with amild oxidant such as manganese dioxide, or the reagent formed bydissolving aluminium tort.- butoxide in a mixture of acetone andisopropanol, to give the 6fl-methyl-3-oxo-A -steroid which may then beisomerised to the 6a-methyl epimer by alkaline or acidic reagents.

In a further method of preparing the 6u-methyl-3-oxo- M-steroids of theandrostane and pregnane series, a 5mhydroxy-6fl-methyl-3-oxo-steroid maybe treated with an acidic dehydrating agent such as, for example, a verydilute solution of hydrochloric acid in an alkanol containing up to fourcarbon atoms or with aluminium tert.- butoxide in toluene, whendehydration and epimerisation will occur to give the6a-methyl-3-oxo-M-steroid.

Hydroxyl groups (other than those at C and C and oxo-groups (other thanthat at C present in the intermediates leading to (1) which may undergochange during the oxidation and dehydration reactions, will naturally beprotected in suitable manner by methods well known to those skilled inthe art, and subsequently regenerated.

The choice of procedure for the preparation of any particular6m-methyl-3-oxo-A -steroid described herein depends upon the nature ofthe substituents borne by the immediate precursor.

Following is a description by way of example of methods of carrying the.invention into effect:

EXAMPLE 1 6a-methyltest0sterone 6fl-methyltestosterone (100 mg.),prepared by the method set forth in copending application Serial No.590,119, filed on June 8, 1956, now abandoned, in methanol .(36 ml.) washeated with potassium hydroxide (400 mg.) under reflux in a stream ofnitrogen for 20 hours. After dilution with water and acidification withacetic acid, the product was extracted with ether. Removal of the etherleft a crystalline residue which was purified from ethanol to give6a-methyltestosterone, M.P. 154 to 155 C., [M (0., 0.34 in chloroform),h 241 mg (4.2) in isopropanol.

EXAMPLE 2 6mmethylnm1r0st-4-enc-3:I 7-dione (a) A solution of5a-hydroxy-6fi-methylandrostane- 3: 17-dione (400 mg.) in dry toluene(40 ml.) was slowly distilled until a few mls. of solvent had beenremoved. A solution of aluminium tert.-butoxide (800 mg.) in toluene wasadded and distillation continued for a further 25 minutes. Rochelle saltsolution was added and the product isolated with ether. the residue wasdissolved in benzene and percolated through a short column of alumina.crystallisation from acetone/hexane gave6a-methylandrost-4-ene-3:17-dione, needles or prisms, MP. 167 to 168 C.,M1 +172 (c., 0.344 in chloroform).

(b) 6fi-methylandrost-4-en-3:17-dione (25 mg.) in methanol (9 ml.) wasrefluxed for 19 hours under nitrogen with potassium hydroxide mg.) inwater (1 ml.). The mixture was neutralised with acetic acid, and theproduct isolated with ether. 6a-mcthylandrost-4-en-3:l7- dione wasobtained, crystallising from acetone/hexane in needles, MP. 162 C., notdepressed on admixture with a specimen prepared by method (a) above.

EXAMPLE 3 I 7fl-hydr0xy-6 m1 7 a-di methylandrosl-4-en-3-0ne (a) Asolution of 6p:l7a-dimethylandrostane-3fl:5m:

l7fl-triol (1.2 g.), prepared by the method set forth in Afterevaporation of the ether;

reflux for 45 minutcs.

copending application Serial No. 587,447, filed on May 28. 1956, nowPat. No. 2,915,364, in cyclohexanone (8.2 ml.) was added 10 a solutionof aluminium tert.-hutoxide (1.1 g.) in toluene (5 ml.) and the mixtureheated under Benzene (ca. 50 ml.) was added, and the solution washedwith dilute sulphuric acid and water. The solution was steam-distilledfor 4 hours then extracted with ether. The extract was washed withwater, dried and evaporated. The residue in benzene was run through acolumn of alumina (10 g.) and the resulting oily product wascrystallised from acetone/hexane. 17fl-hydroxy-6a:17a-dimethylandrost-4en 3 one (6a217a-dimethyltestosterone) separated in needles, M.P. 134 to135 C., [all +49 (c., 0.421 in ethanol), a m (4.19) in isopropanol.

(b) A solution of 5a:17p-dihydroxy-6B:17a-dimethy1- androstane-3-one(700 mg.) and aluminium tert.-butoxide (1.4 g.) in toluene (110 ml.) wasrefluxed for 1 hour, cooled, shaken with aqueous Rochelle salt, andextracted with ether. The ethereal solution was washed and the solventsremoved by steam-distillation. The product, in benzene, was percolatedthrough a short column of alumina to give an oil which crystallised fromacetone/hexane. 6a:l7a-dimethyltestosterone formed needles, M.P. 129 to131 C., alone or on admixture with a specimen prepared by method (a)above.

(c) 5112175 dihydroxy 613: 17c: dimethylandrostan- 3-one (2.12 g.) inethanol (140 ml.) was heated under reflux with concentrated hydrochloricacid (0.35 ml.) for 30 minutes. After dilution with water (1 litre), themixture was left overnight at C., and the precipitated crystalscollected and purified from acetone/ hexane. 61111711-dimethyltestosterone formed prisms, M.P. 136 to 137 C.,

[ 1 +66 (c., 0.88 in chloroform).

EXAMPLE 4 6l1-methylethistcrone (a) 6fl-methylethisterone (1.5'g.),prepared by the method set forth in copending application Serial No.590,119, filed on June 8, 1956, in aqueous ethanol (60 ml. of 95%)containing potassium hydroxide (1.5 g.) was heated under reflux forhours. The mixture was diluted with water, the product extracted withether, and the washed and dried extract concentrated to low volume. Thecrystalline deposit was purified from aqueous methanol to give17a-ethinyl-17fi-hydroxy-6a-methylandrost- 4-en-3-one(tia-methylethisterone), prisms, M.P. 195 to 197 C., [a] +34.5 (c., 0.87in chloroform).

(b) A solution of 5a:17/3-dihydroxy-17a-ethinyl-6)3-methylandrostan-3-one (8.5 g.) in ethanol (250 ml.) was treated with 6drops of concentrated hydrochloric acid and the mixture refluxed for 30minutes. The product was taken into ether (1.5 litres), and the solutionwashed, dried, and concentrated to low volume. 6a-methylethis tcroneseparated in dense crystals, M.P. 195 to 197 C., identical with a sampleprepared by method (a) above.

EXAMPLE 5 6a-methylpr0gesterone (a) 6fl-methylprogesterone (600 mg.),prepared by the method set forth in copending application Serial No.

, 4 590,119, filed on June 8, 1956, in methanol (25 ml.) was heated withpotassium hydroxide (500 mg.) in water (5 ml.) under reflux in a streamof nitrogen for 16 hours. The product was isolated with ether andyielded 6a-methylpregn-4-cne-3z20xlione (6a mcthylprogestcrone) as flakyneedles, M.P. 122 to 123 0., tab" +177 (c., 1.05 in chloroform), aftercrystallisation from aqueous methanol.

(b) A solution of 5a-hydroxy-6f3-mcthylallopregnane- 3:20-dione (500mg.) in ethanol (40 ml.) was treated with 3 drops of concentratedhydrochloric acid and the mixture refluxed for 30 minutes. Concentrationof the solution, followed by addition of water and cooling, gaveoa-methylprogesterone, M.P. 121 to 123 C., after recrystallisation fromaqueous methanol.

(c) Gfl-methylprogesterone (1 g.) in ethanol ml.) was treated with 4drops of concentrated hydrochloric acid and the mixture refluxed for 30minutes. 6a-methy1 progesterone, M.P. 121 to 123 C., was obtained afterworking up as described in (b) above.

We claim:

1. 6a:17a-dimethyltestosterone.

2. 17a ethinyl 17 .3 hydroxy 6a methylandrost- 4-en-3-one.

3. oa-methylprogesterone.

4. A method for the preparation of 6a-methyl-3-oxo- A -steroids of theandrostane and pregnane series which method comprises treating thecorresponding 6B-methyl- 3-oxo-A -steroid with a reagent selected fromthe group consisting of strongly ionizable acids and alkalis underreflux and under nitrogen for several hours.

5. A method for the preparation of 6a-methyl-3-oxo- A -steroids of theandrostane and pregnane series which method comprises treating thecorresponding Set-hydroxy- 6fl-methyl-3-oxo-stcroid with aluminiumtert.-butoxide in toluene to give the 6m-methyl-3-oxo-A -steroid.

6. A method for the preparation of 6a-methyl-3-oxo- M-steroids of theandrostane and pregnane series which method comprises treating thecorresponding Sci-hydroxy- 6fl-methyl-3-oxo-steroid with an acidicdehydrating agent comprising a strongly ionized acid in an alkanolcontaining up to four carbon atoms to effect dehydration andepimerization to give said 6a-methyl-3-oxo-A steroid.

7. A method for the preparation of 6a-methyl-3-oxo-A steroids of theandrostane and pregnane series, which method comprises treating acorresponding 3flz5a-dihydroxy-6B-methyl steroid of said series with analuminum alltoxide in cyclohexanone and toluene under reflux.

References Cited by the Examiner UNITED STATES PATENTS LEWIS GOTTS,Primary Examiner.

LESLIE H. GASTON, ELBERT L. ROBERTS,

Examiners.

O. RAMSEY, B. G. COLLEY, R. E. WEXLER,

. Assistant Examiners.

3. 6A-METHYLPROGESTERONE.